This invention relates to certain esters and amides of (+) suprofen having enhanced delivery characteristics on topical administration to the eye. This invention also relates to pharmaceutical compositions comprising such suprofen derivatives and to methods of using them when indicated to achieve an anti-inflammatory effect on topical delivery to the eye.
U.S. Pat. No. 4,559,343, issued Dec. 12, 1985, discloses pharmaceutical compositions and methods of treatment employing various known, nonsteroidal analgesic/anti-inflammatory agents, including racemic suprofen. To the extent that this patent teaches tha ophthalmic pharmacology of racemic suprofen, it is incorporated herein by reference since such disclosure can be applied with efficiency in teaching the pharmaceutical compositions and methods of treatment employing the (+) suprofen esters and amides of the present invention. However, as is disclosed in U.S. Pat. No. 4,559,343, suprofen per se at appropriate dosage concentrations for ophthalmic delivery is generally perceived as stinging. Thus, it was the purpose of the disclosed and claimed invention in U.S. Pat. No. 4,559,343 to define formulations which tend to decrease the stinging sensation associated with the application of racemic suprofen to the eye. The pharmaceutical compositions and methods of treatment of U.S. Pat. No. 4,559,343 employ a complex of suprofen and a xanthine derivative, such as, caffeine to achieve the stated objective. The consensus of the clinical experience involving the disclosed xanthine-suprofen compositions of U.S. Pat. No. 4,559,343, however, is that the alleged comfort formulation is only moderately improved. And this is particularly true in situations wherein the exquisitely sensitive cornea is rendered even more sensitive through comprised health or trauma.
Unexpectedly, it has been discovered that substantially all (ca. 70-fold) of the ophthalmic anti-inflammatory activity of racemic suprofen resides in its (+) enantiomorph. Further, ophthalmic formulations comprising (+) suprofen substantially free of (-) suprofen and at concentration level of approximately one-half of the prior recommendations for the racemic mixture are equivalent in efficacy to such prior art formulations; and further such formulations may be employed at this one-half strength level without the acute stinging sensation which attends the use of full strength formulations of racemic suprofen. Such isomeric effect is also seen for the (+) suprofen esters and amides of the present invention.
The expression, relative to the purity of (+) suprofen compounds, that it be "substantially free of (-) suprofen" means that the corresponding (-) suprofen enantiomorph is co-present is such mixtures at a concentration level of from 0 to 5%. Preparations of such substantially pure forms of (+) suprofen for starting material in preparing the esters and amides of the present invention can be achieved by stereo-selective synthesis, or (+) suprofen can be isolated from the racemic mixture by conventional methods, such as, forming diastereoisomeric salts with optically active organic amines, for example, alpha-methylbenzylamine, which, in fact, is a published accomplishment. Reference is made to U.S. patent application Ser. No. 933,840, filed Nov. 24, 1986 entitled Ophthalmic Anti-Inflammatory Compositions Comprising (+) Suprofen, which application is incorporated herein by reference.
Suprofen, alpha-methyl-4-[2-thienylcarbonyl] benzeneacetic acid, is an inhibitor of prostaglandin biosynthesis with analgesic, antipurretic and anti-inflammatory properties. Suprofen was developed by Janssen Pharmaceutica; Beerse, Belgium, as disclosed in P. G. H. Van Daele, J. M. Boey, V. K. Sipido, M. F. L. De Bruyn, and P. A. J. Janssen; Arzneim-Forsch, (Drug Res.), 25 (10), 1495 (1975). This article is incorporated herein by reference to the extent that it teaches the preparation of suprofen and techniques of synthesis of certain esters and amides of suprofen which are described in that article, and which techniques, by analogy, provide an enabling disclosure on how to prepare the compounds of the present invention. The esters and amides of (+) suprofen of the present invention are not disclosed by the incorporated by reference article and further the species disclosed in the prior art do not possess an attribute unique to the (+) suprofen species of the present invention which property relates to their ability to be transported across the cornea and thus made available for the ophthalmic anti-inflammatory effect when administered to the eye. Beyond the disclosed original article relating to suprofen esters and amides, there appears to be no relevant prior art relating to suprofen derivatives and the ability of such suprofen species to be transported across the cornea for purposes of enhancing drug delivery. Cross reference, however, is made to applicants' co-pending, concurrently filed, commonly assigned U.S. patent application Ser. No. 06/948,184 also entitled Suprofen Esters and Amides as Ophalmic Anti-Inflammatory Agents.